Old and New Facts and Speculations on the Role of the B Cell Receptor in the Origin of Chronic Lymphocytic Leukemia

Abstract

The engagement of the B cell receptor (BcR) on the surface of leukemic cells represents a key event in chronic lymphocytic leukemia (CLL) since it can lead to the maintenance and expansion of the neoplastic clone. This notion was initially suggested by observations of the CLL BcR repertoire and of correlations existing between certain BcR features and the clinical outcomes of single patients. Based on these observations, tyrosine kinase inhibitors (TKIs), which block BcR signaling, have been introduced in therapy with the aim of inhibiting CLL cell clonal expansion and of controlling the disease. Indeed, the impressive results obtained with these compounds provided further proof of the role of BcR in CLL. In this article, the key steps that led to the determination of the role of BcR are reviewed, including the features of the CLL cell repertoire and the fine mechanisms causing BcR engagement and cell signaling. Furthermore, we discuss the biological effects of the engagement, which can lead to cell survival/proliferation or apoptosis depending on certain intrinsic cell characteristics and on signals that the micro-environment can deliver to the leukemic cells. In addition, consideration is given to alternative mechanisms promoting cell proliferation in the absence of BcR signaling, which can explain in part the incomplete effectiveness of TKI therapies. The role of the BcR in determining clonal evolution and disease progression is also described. Finally, we discuss possible models to explain the selection of a special BcR set during leukemogenesis. The BcR may deliver activation signals to the cells, which lead to their uncontrolled growth, with the possible collaboration of other still-undefined events which are capable of deregulating the normal physiological response of B cells to BcR-delivered stimuli.

Impending splenic rupture as indicator of atypical chronic lymphocytic leukemia: A case report from Saudi Arabia

“…Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm of the blood that predominantly affects elderly population (≥ 60 years) [ 1 , 16 , 17 ]. The patient may experience progressive enlargement of the lymph nodes, symptoms of anemia, bleeding or blood clots, fever, nighttime sweetness, body pain, or early satiety.…”

“…This health condition can be suspected by a high WBC count, in particular, lymphocytes (≥5000 B-lymphocytes/μL), persisting for at least three months. Further factors can be the clonality of circulating B-lymphocytes, as confirmed by flow cytometry data with expansion of CD19+, CD5+, and CD23+ B-lymphocytes in a blood sample, bone marrow, or tissue biopsy [ 10 , 11 , 16 , 17 ].…”

Assessment of Impact of Human Leukocyte Antigen-Type and Cytokine-Type Responses on Outcomes after Targeted Therapy Currently Used to Treat Chronic Lymphocytic Leukemia

“…Accessory cells such as T cells, bone marrow stromal cells, and dendritic cells produce several factors that function as pro-survival elements in CLL by inhibiting spontaneous programmed cell death [ 14 ]. Alterations in lymphocyte and accessory cell subsets along with variations in cytokine expression can contribute to infectious complications, which are a common cause of death in patients with CLL [ 15 ]. Furthermore, patients with progressive CLL exhibit a higher number of specific T cells that produce certain cytokines than those with a mild course of the disease.…”

Normal B cells express ZAP70 in chronic lymphocytic leukemia: A link between autoimmunity and lymphoproliferation?

“…Zeta‐chain‐associated protein of 70 kDa (ZAP70), a protein tyrosine kinase required for TCR signaling, is abnormally expressed in some CLL B cells and is a surrogate prognostic marker discriminating between mutated and unmutated immunoglobulin heavy variable (IGHV) gene CLL subsets 6–8 . ZAP70+ CLL cells have survival advantages, possibly through ZAP70‐related altered BCR signaling after BCR ligation, 9–11 which is known to play a role in CLL pathogenesis 12–17 …”

“…[6][7][8] ZAP70+ CLL cells have survival advantages, possibly through ZAP70-related altered BCR signaling after BCR ligation, [9][10][11] which is known to play a role in CLL pathogenesis. [12][13][14][15][16][17] Furthermore, CLL is associated with the development of autoimmune disorders, especially autoimmune cytopenia (AIC), such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), [18][19][20][21] that can occur at any time during CLL evolution, even in "preleukemic" monoclonal B-cell lymphocytosis. 22,23 ZAP70 expression by CLL cells is the most discriminative parameter between CLL patients with or without AIC.…”